Gender differences in vitiligo: psychological symptoms and quality of life assessment description

Objective Assuming that the difference exist in the manifestation of psychological suffering among genders, the purpose of this review is to summarize the current knowledge on gender differences in vitiligo quality of life and psychological assessment. Methods We searched in PubMed, Scopus, and Web of Science databases for original articles in English language. Results were screened according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA checklist). Results The study yielded 107 results; 12 articles have been evaluated as eligible. Each eligible study has been screened and analyzed. The study’s qualitative evaluation revealed that 8 papers were classifiable as satisfactory, 4 were classifiable as unsatisfactory. The agreement between the coders was high (% agreement = 84.6%; Cohen’s kappa = 0.79). All considered researches (100%) were cross-sectional studies, based on self-report questionnaires. From our analysis, women with vitiligo had a higher risk to experience lower quality of life, and worse mental health in a wide range of psychopathology symptoms than men. A wide heterogeneity of tools is used to investigate the quality of life and psychological symptoms among these patients. Conclusion Unfortunately, there are few explanatory models proposed in the literature to rationalize these findings. It will be important to investigate in further researches the specific influence of known risk factors for psychopathology in this population to better explore these phenomena.


Eligibility criteria
In this review we included all the cross-sectional, case-control, or cohort studies that assessed gender differences in patients with vitiligo using validated methods.Case reports, case series, review articles, letters to the editor, and psychometric studies were excluded.The databases selected to perform this work did not report gray literature; for this reason, unpublished studies were not included in this review.The data found in conference papers or abstract books have not been reported as well, because are usually reported later in published articles.

Selection of studies and data extraction
To select potential studies, the title, the abstract and keywords of each article found in each database were reviewed.In this phase article duplicates (N = 77) have been removed.Eighteen records were further excluded because the full-text was not available, or results were not focused on gender differences, or the full text was not in English.Twelve studies were included in the qualitative synthesis, and all of them were included in the quantitative analysis.
Data from the studies of interest were extracted and inserted in a structured dataset; core information about each publication have been addressed using a standardized reporting form.All the authors reviewed the summary table of the included studies.

Quality assessment
The quality of the eligible articles was independently assessed by the first and the last authors (TS and DA) using the Newcastle-Ottawa Scale (NOS) modified for the assessment of the quality of crosssectional studies.This methodological instrument has been previously adopted in meta-analytic epidemiology studies (Stang, 2010) and in systematic reviews on immune-mediated chronic skin diseases (Machado et al., 2019).The scores are comprised between 0 and 10, and a higher score is indicative of a higher quality of the study (i.e., Very Good Studies: 9-10 points; Good Studies: 7-8 points; Satisfactory Studies: 5-6 points; Unsatisfactory Studies: 0-4 points).In case of incongruity between reviewers, agreement was reached after in-person discussion.

Results
The flowchart shown in Figure 1 details each step of the study selection process.The results in each step have also been specified in the figure.Quantitative synthesis of the selected study features has been reported in Table 1.Inter-coder agreement was high when the independent coders (T.S. and D.A.) examined the full text of the 12 articles identified as eligible, the agreement between the coders was high (% agreement = 84.6%;Cohen's kappa = 0.79).Disagreements were resolved through discussion.According to McHugh (2012), from the study's qualitative evaluation (McHugh, 2012), eight papers are classifiable as satisfactory studies, while five are classifiable as unsatisfactory.A specifically description of each study's evaluation is reported in Table 2.

Features of included findings
All collected records are cross-sectional, observational studies, except for Trapp et al. (2015) that is described as age and gender matched "exploratory case control study, " respectively.The total sample collected in this review includes 2,264 participants with vitiligo; 91 with Acquired Dermatological Macular Hyperpigmentation; 86 with Melasma; 128 with Psoriasis; and 99 were healthy controls.
In line with the purpose of this review, we focused only on data related to the people who suffered from vitiligo.Females were 1,568 (66.0%),the minimum age of the analyzed sample was attested at 16 years old, the maximum age was attested at 84 (Ingordo et al., 2014).Four studies of 12 (Kent and Al'Abadie, 1996;Schmid-Ott et al., 2007;Sampogna et al., 2008;Ingordo et al., 2014) recruited, among adult, also pediatric population.In Table 1 we described in detail the sample population for each selected study.

Characteristics of quality of life assessment tools used in screened publications
The scientific contributions analyzed in this review reveal the wide heterogeneity of the tools used to investigate the Health-Related Quality of Life (HRQoL) and psychological symptoms among people suffering from Vitiligo.All the questionnaires used through the studies are self-administered, most of them are adapted and validated in the language of the population to which they refer.
The detailed features of these tools have been reported in Table 3.
The VitiQol, the disease-specific tool for vitiligo, used in a single study of those eligible (Abdullahi et al., 2021), showed that the HRQoL was significantly more impaired in women than men (p = 0.037), with the stigma component as the major contributor to the high mean VitiQoL (p < 0.001).T-tests revealed a significant influence of gender on the QES "stigmatization retreat" (P = 0.03) and "stigmatization composure" (p < 0.001) scales.
ACS revealed significantly lower results for men on the "helplessness" scale and itch-scratch circle coping strategies (p < 0.01).
Coping capacity, Stigmatization, Helplessness The other HRQoL tool used in another single study of the eligible (Sampogna et al., 2008) was the Skindex-29.In this study, Sampogna et al. (2008) found a significant difference in Skindex-29 scores, with worse outcomes for women in items #2, #6, #11, #12, #13, #15, #26, #28, and for the whole emotions and functioning subscale (p < 0.05), but not for the symptom's subscale.This result is in accordance with previous research on gender differences in chronic autoimmune dermatology patients (Samela et al., 2023).

Differences among genders detected in psychological symptomatology assessment tools
The studies identified in this systematic review used a huge range of psychologic tools, and explore several psychologic features, both dispositional and situational.For an extensive description of constructs assessed in each study (see Table 1).

Discussion
The aim of our systematic review, conducted according to the PRISMA guidelines, was to assess the differences among genders in HRQoL and in psychologic symptoms among persons with vitiligo.The qualitative assessment of the 12 eligible studies (Kent and Al'Abadie, 1996;Ongenae et al., 2005;Al Robaee, 2007;Schmid-Ott et al., 2007;Sampogna et al., 2008;Ingordo et al., 2014;Krüger and Schallreuter, 2015;Trapp et al., 2015;Dabas et al., 2020;Abdullahi et al., 2021;Do Bú et al., 2022;Ning et al., 2022) revealed a wide heterogeneity in term of methodology, as well as in terms of quality among studies.The design of all the studies included in the review was cross-sectional.Also, the pediatric population was included in several reports.For these reasons we chose to discuss our results by symptom or characteristic, rather than by assessment tool.

Personality traits
Personality traits in patients with vitiligo were assessed in only one study (Do Bú et al., 2022).Their results highlighted the presence of significant differences between genders, in fact women tended to present higher level of neuroticism than men, as also occurs in the general population (Lynn and Martin, 1997).However, high levels of neuroticism could interfere with the patients' psychological adaptation to vitiligo (Bonotis et al., 2016), and could increase the risk of a worse adaptation to the disease for women than men.

Alexithymia
Although the psychoanalytic tradition has identified several types of alexithymia (Sifneos, 1973;Freyberger, 1977;Honkalampi et al., 2000), and Honkalampi et al. (2000) have identified changes in the levels of alexithymia over time, Sifneos (1973) and other recent authors have defined alexithymia as a personality trait (Kumari et al., 2023).Beyond the unresolved theoretical discussion, in our results only one study, by Sampogna et al. (2008) alexithymia in persons with vitiligo, finding a higher prevalence of this trait in their patients (i.e., 24%), compared to the general populations (approximately 10%).No differences among genders were detected.This result is in contrast with what is asserted in the literature for the general population, in which usually men score higher than women on measures of alexithymia (Levant et al., 2009).

Coping strategies
Two studies assessed coping strategies in persons with vitiligo (Schmid-Ott et al., 2007;Krüger and Schallreuter, 2015) using the ACS.Krüger and Schallreuter (2015) found that female patients tend to have worse coping strategies than men, particularly in the ACS subscale that assesses emotional and physical symptomatology of general disturbance in coping with the emotional distress because of the disease.Conversely, Schmid-Ott et al. (2007) found worse coping ability in men than women, especially in Itch-Scratch Cycle (which reflects the inability to cope with itching, and feelings of helplessness concerning the cycle of itching and scratching) and Helplessness (that concerns the experience of loss of hope about the recurrence of the skin condition).

Stigmatization
The experience of stigmatization, evaluated through the VitiQol (Abdullahi et al., 2021) and the QUES (Schmid-Ott et al., 2007).Schmid-Ott et al. (2007), showed that women tend to experience a lack of self-perceived physical attractiveness or sexual desirability because of the skin disease more frequently than men.They were also more worried than men about their skin disease.It is possible to hypothesize that women struggle more about their skin problems because appearance norms for women are more rigid, homogeneous, and pervasive than those for men (Buote et al., 2011).Everyday exposure to norms and social pressure may exacerbate negative emotions, maladaptive cognitions, with worse negative mental health outcomes in women (Łakuta et al., 2017).

Rumination
Only one study (Do Bú et al., 2022) highlighted the presence of high levels of rumination among persons who suffered from vitiligo, in fact both women and men presented high levels of this manifestation.However, for women, stress and reflection (i.e., a rumination component) seem to be important mechanisms in predicting anxiety and depression symptoms, whereas brooding (i.e., the other rumination component) is associated with the same symptomatology in men.According to these results, it is possible to hypothesize that women tend to engage cognitive problem-solving strategies to struggle with depressive and anxiety symptoms, whereas men seem to adopt strategies more related to a passive comparison of their current situation with some unachieved standard, in dealing with depression and anxiety (Verstraeten et al., 2010).

Depression
Depression has been evaluated through different tools in five of the eligible studies.Only Dabas et al. (2020) did not describe differences among genders in this clinical variable.Conversely, Sampogna et al. (2008), Krüger and Schallreuter (2015), Do Bú et al. (2022), and Ning et al. (2022), and consistently highlighted a significant higher score in depression symptomatology in women than in men.A comprehensive meta-analysis by Wang et al. (2018) confirmed that female patients with vitiligo were more likely to show depression when compared with male patients.It is well known that depression accounts for a substantial part of the psychosocial burden of chronic disorders (Gold et al., 2020).However, concerning the specific case of skin disorders, feelings of shame could increase social avoidance behaviors and withdrawal, which, in turn, might result in reduced perceived social support, and increasing hopelessness.Helplessness is, in fact, also detected by Schmid-Ott et al. (2007) and is significantly higher in women than men.

Anxiety
The general prevalence of anxiety among vitiligo patients worldwide (i.e., 35.8%) was comparable to other severe skin disorders (Kussainova et al., 2020), and is significantly higher in females than in males (Kussainova et al., 2020;Liu et al., 2021).This difference has been confirmed in Do Bú et al. ( 2022) and Ning et al. (2022), but not in Dabas et al. (2020).It is possible to deduce that patients with vitiligo experienced a substantial burden because of anxiety (Liu et al., 2021).Several hypotheses may explain the increased prevalence of anxiety disorders among individuals with vitiligo; for example, female patients with skin depigmentation suffer from more discrimination in daily life (Chaturvedi et al., 2005).In partial accordance with our data, and according to the literature, females could be at higher risk of developing social anxiety symptoms, due to greater appearance awareness, feeling of looking unattractive, and lower self-confidence (Sawant et al., 2019).These negative effects, according to the Cognitive Behavioral model of social anxiety, could result in avoidance behaviors (e.g., avoid meeting new people, being sexually inhibited), that bolster social anxiety symptomatology (Heimberg et al., 2010).

Stress
A relevant corpus in the literature points the attention on psychological stressors that may play a role in vitiligo and, in general, in skin disorders (Papadopoulos et al., 1998;Silverberg and Silverberg, 2015), even if this cause-effect mechanism is controversial (Picardi and Abeni, 2001).Stressful life events have been considered as antecedent factors to the onset of vitiligo (Silverberg and Silverberg, 2015).Moreover, from a bio-psychological point of view, chronic stress could have a role in the pathogenesis of vitiligo (Miniati et al., 2012;Cupertino et al., 2017).In neither of selected study biological stress-related parameters of hormonal imbalances were detected, but it has been observed the presence of high levels of distress in vitiligo female patients compared to the test norms (Do Bú et al., 2022;Ning et al., 2022).Only one study reported significantly higher stress levels in women than men (Do Bú et al., 2022).
To the best of our knowledge, and based on what emerged from our systematic review, women with vitiligo have a higher risk to experience low quality of life, and worse mental health in a wide range of psychopathology symptoms than men.Unfortunately, there are few explanatory models proposed in the literature to rationalize the greater prevalence of psychopathological symptoms in women compared to men in vitiligo.This could be explained by the crosssectional nature of the considered studies, and because of the used assessment methods, which mainly investigate the presence of these symptoms only at the moment of assessment, not exploring the factors that may affect the emergence of these issues.It will be important to investigate in further researches the specific influence of, for example, the disease duration, comorbidity, socio-demographic features, personality traits, components of attachment behavior, and other known risk factors for psychopathology in this patient population to better explore these phenomena.

Study limitations and conclusion
It is important to note that some issues limit the generalizability of our findings.A single search string was used in the databases used for our systematic review.No gray literature databases have been considered.We tried to minimize publication bias by rigorously following internationally accepted criteria of study selection for systematic reviews.No data referring to non-binary or gender-fluid patients have been identified in the included studies.Very few studies report the word "gender" or "gender differences" in the aims or in the keywords.Most differences in the scores between the genders reported in this paper were abstracted from one single eligible article.
Our study differed from previous studies and added to previous findings by investigating directly the most used tools to study QoL and psychopathological symptoms in people who suffer from vitiligo, with a specific focus on gender differences.Such differences seem to exist, in fact, with most reports showing a larger impact of vitiligo on the psychological well-being among women than in men.However, the vast methodological heterogeneity of the reports, e.g., in terms of study population, sample size, investigated construct, patient-reported outcomes tools used-does not allow to perform a meta-analysis or to compute summary measures such as effect sizes.Not only that, but such heterogeneity is so extreme that each investigated construct is based on an insufficient number of studies (i.e., often in a single study) to make evidence-based conclusions about the validity and generalizability of these findings.
Given the relevant impact of vitiligo on the psychosocial wellbeing of patients, it would be advisable to identify a standardized core of patient-reported outcomes so that more meaningful comparisons may be made across different studies.

FIGURE 1 PRISMA
FIGURE 1PRISMA flow diagram of psychosocial studies on gender differences in vitiligo retrieved using the search string detailed in the Methods section.

TABLE 1
Summary of collected and analyzed data from psychosocial studies on gender differences in vitiligo included in this review.

TABLE 2
Study assessment of included study using the Newcastle-Ottawa Scale adapted for cross-sectional studies.
Representativeness of the case; 2. Sample size; 3. Non-Response rate; 4. Ascertainment of the screening/surveillance tool; 5.The potential confounders were investigated by subgroup analysis or multivariable analysis; 6. Assessment of the outcome; 7. Statistical test.

TABLE 3
Detailed description of the assessment tools from psychosocial studies on gender differences in vitiligo included in this review.